International open-label phase I dose escalation study of dinutuximab beta in combination with vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide in pediatric, adolescent, and adult patients with GD2-positive Ewing sarcoma

Prior treatment

• Active and uncontrolled CNS metastases (indicated by clinical symptoms, cerebral edema, corticosteroid and/or anticonvulsant requirement, or progressive disease); for controlled CNS metastases, patient should have been off corticosteroids for at least 28 days without overt evidence of significant neurological deficits prior to enrollment

Other illness

• Relapsed or refractory disease state
• Patients with hypersensitivity against at least one component of the investigational medicinal product
• Significant illnesses and/or any of the following: significant psychiatric disabilities or uncontrolled seizure disorders; active uncontrolled peptic ulcer disease; clinically significant neurologic deficit or objective peripheral neuropathy; clinically significant, symptomatic fluid in a third space
• Diagnosis of any malignancy other than the disease under study
• Any other medical or social condition deemed by the Investigator to be likely to interfere with a patient’s ability to cooperate and participate in the study or interfere with the interpretation of the results
• Active, uncontrolled infection or an unexplained fever >38.5°C which in the Investigator’s opinion might compromise the patient’s participation in the study or affect the study outcome

Lab values

• Significant cardiac conduction abnormalities, including known familial prolonged QT syndrome, or screening QTc >480 msec

Other

• Chronic Grade ≥2 diarrhea

• Histologically confirmed, newly diagnosed Ewing Sarcoma (m/f/d) or so-called Ewing-like sarcoma (i.e. translocation-positive small blue round cell sarcoma other than Rhabdomyosarcoma) of bone and / or soft tissue with evidence of EWS translocation by fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (RT-PCR), or next-generation sequencing (NGS) assay
• Availability of fresh frozen tumor tissue for central GD2-detection
• Age ≥12 months
• Start of first line treatment according to standard induction treatment (Cycle 1-4: VDC – IE – VDC – IE)
• Wash-out phase with a minimum of 14 days after the last dose of the last chemotherapy
• Lansky (<16 years) Performance Score ≥70% or ECOG (≥16 years) ≤ 2
• Adequate bone marrow function as evidenced by meeting all the following requirements: white blood cell count > 2000/µl, ANC ≥1000 cells/μL (G-CSF allowed), platelet count 75,000 cells/μL without the use of platelet transfusion within the last 2 days, hemoglobin ≥9 g/dL without the use of red blood cell transfusion within the last 2 days
• Adequate renal function: creatinine clearance or glomerular filtration rate (GFR) > 60 mL/min/1.73 m2
• Adequate hepatic function as evidenced by meeting all the following requirements: serum total bilirubin ≤1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN
• Adequate cardiac function: confirmed by echocardiography with a left ventricular ejection fraction (LVEF) of ≥ 50%
• No known active HIV, HBV, or HCV infection
• No severe neurological impairment, particularly no motor or sensory deficits, except for neurological deficits caused by Ewing sarcoma
• Female patients of childbearing potential must present with a negative serum pregnancy test and agree to employ adequate birth control measures for the duration of the study and until 3 months after the end of treatment. Female patients who are lactating must agree to stop breast-feeding from the start of study treatment until 1 month after the end of treatment
• Patient or their legal representative is willing and able to comply with the requirements of the study protocol
• High risk stratification (metastatic disease)
• Centrally confirmed GD2-positive tumor (biopsy of original and/or residual tumor or liquid biopsy in peripheral blood)